PROJECT SUMMARY of the administrative supplement The objectives of the parent R01 grant are 1) to develop and evaluate the transport, delivery, release on demand and efficacy of nanoformulation containing cannabinoid receptor modulators to activate latent HIV infection, eradicate HIV and protect from HIV/cannabinoid-induced neuronal deficits using an in-vitro BBB-HIV infection cannabinoid model, 2) to evaluate the in vivo efficacy of the developed nanocarrier in HIVE SCID cannabinoid mouse model, and 3) to monitor the neurobehavioral modulations induced by nanoformulation in HIVE SCID cannabinoid mouse model. Thus the three major focuses in the parent R01 are the HIV, magneto- electric nanoparticle (MENP)-based drug delivery and the cannabinoid pathway. Here we want to broaden the scope of these three major focuses by also evaluating the potential of cannabinoid system for therapy during the comorbidity of HIV and Alzheimer?s disease (AD) which is emerging as a major health problem in recent years. Following the introduction of HAART, many HIV patients live longer and thus enter an age when the risk of developing AD increases exponentially. So far, the apoE4 allele is the strongest genetic risk factor identified in sporadic AD patients, and there is also a strong association between apoE4 and the rate of HIV-1 disease progression, suggesting a strong relationship between HIV infection and AD pathogenesis. This is not surprising given the fact that exposure to HIV particles and HIV proteins can directly or indirectly modulate the amyloid and Tau proteins, the two hallmark features of AD. Also, HIV-infected elders have a higher rate of meeting criteria for mild cognitive impairment (MCI). Therefore, we hypothesize a synergistic effect of the comorbidity of HIV and AD on the common neuropathological features such as A?, tau, neurodegeneration, and synaptic loss. Further, treatment with cannabinoid activators through the developed nanoformulation will mitigate these neuropathological features. We will test this hypothesis by generating 3xTg-AD/iTAT bigenic mice (+/- doxycycline) and compare the results with 3xTg-AD and iTAT (+/- Dox) single transgenic lines. In specific aim 1, using MENP technology, we will evaluate the role of cannabinoid CB1 and CB2 receptor agonists and antagonists on the subventricular zone (SVZ) and subgranular zone (SGZ) adult neurogenesis as well as levels of A? and hyperphosphorylated tau. In the specific aim 2, we will evaluate the role of ECS on the dendritic spine density and number of synapses and correlate with learning and memory skills. Since we plan to test the cannabinoid system directly in a mouse model of HIV (iTAT) and AD (3xTg-AD) and address three key questions in HIV/AD research, i.e., HIV and AD comorbidity, cannabinoid multitarget pathway and efficient brain penetration, this administrative supplement request is directly related to Alzheimer?s disease and related dementias (ADRD). If the liposomal-MENP drug delivery in this HIV/AD comorbidity mouse model is successful, it may also be extended to other neurological diseases in future studies.